As I mentioned in Part I of this three-part blog-a-thon, HIV is far more clever and cunning than any of us realized in the early days of the epidemic, when we all assumed that with the three Ts -- time, talent and treasure -- we could cure HIV in the not-too-distant future. Three decades later, despite billions of dollars and the best efforts of research scientists, HIV still has no cure and has prematurely snuffed out the lives of over 25,000,000 people.

So why don't we have a cure? At the July 1996 International AIDS Conference in Vancouver, scientific evidence was presented that definitively showed effective combination antiretroviral therapy, which included the recently developed protease inhibitors, could reduce HIV in the blood to undetectable levels. Many assumed we merely needed to administer ART for a period of time, perhaps three to five years, in order for the virus to burn itself out and thus for HIVers to be cured. Unfortunately that was not reality, because each time ART was stopped, the virus came roaring back, no matter how long the individual remained undetectable before interrupting ART.

The reason for the resurgence when ART was no longer on board is the same reason curing HIV has been so incredibly challenging: viral reservoirs. So what the heck are they? Let me try to explain. Viruses, such as HIV, are not self-sufficient organisms, like certain bacteria, parasites or other germy illness-causing invaders. A virus is, in essence, just a small package containing a tiny strand of genetic material called DNA. This DNA contains the genetic code for the virus itself. For HIV to cause infection it must find a host (like me, for instance), enter the host's cells (such as my immune system CD4 T cells), and deliver its DNA payload directly into the genetic core (the nucleus) of the host cell, which is where the host DNA is stored. OK so far? Good. Let's proceed.

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DNA is basically a long-chain chemical code that carries the genetic information that allows an organism to operate. It basically instructs the body's machinery, advising it to make proteins and other elements the organism needs to survive and thrive. Each of the trillions of cells in a human body contains a complete copy of its unique DNA. Cool eh? Most cells only use a small portion of the DNA strand. A human DNA strand is nearly six feet long when stretched out. That's several inches taller than me!

And so what does this have to do with HIV reservoirs? Glad you asked! HIV is an unusual virus, because it contains an enzyme (protein) called integrase. Integrase astonishingly "integrates" the small thread of viral DNA directly into the host DNA. Yeah I know, it sounds very sci-fi, doesn't it? The viral DNA then maliciously hijacks a small piece of the host cell's machinery and turns it into a crazed viral Xerox machine. The infected cell begins cranking out new HIV particles with amazing speed and efficiency. Each replication travels through the bloodstream in search of new cells to infect, transforming them into new manic viral copy machines. Frightening, eh?

So what about antiretrovirals? Effective combination ART can shut the copy machines off, halting the mass replication of the virus. But they unfortunately cannot excise the viral DNA from the host cell. The cell remains infected. Some viruses, even nasty ones like hepatitis C, can be eradicated ("cured") if viral replication is effectively turned off for a long enough period of time. But not HIV! As you may have guessed by now, HIV cunningly infects certain cells of the immune system, which are very, very long-lived. These are a subset of so-called memory cells. These memory cells help the body respond quickly to infections it has experienced in the past. It's a nifty immune mechanism, but a small portion of these remarkable memory cells (maybe only one in a million) become dormant sleeper cells. These can remain "asleep" and quiescent for decades. The dormant memory cells that are infected with HIV constitute the "latent HIV reservoir."

When these infected sleeper cells are awakened by a stimulus or immune challenge, they, too, become crazy HIV replication machines, spitting out new infectious HIV particles. Sure, if ART is on board, it can shut off viral replication and the awakened cell will eventually die. But due to the long life of some of these dormant sleeper memory cells, HIVers must stay on ART for decades and decades, essentially a lifetime. This is the crux of why a cure for HIV has been so elusive.

Of course those frustrated with the slow scientific pace toward curing HIV could turn to only one of the dozens of instant HIV cures (for a hefty fee) that are readily available on the Internet. There are a wide variety to choose from. These bogus products claim to immediately cure HIV with a zap of electricity, whiff of ozone or secret mixture of herbs. (See my blog on this topic: "Hocus-Pocus: Quantum Quackery, aka Alternative Medicines for HIV/AIDS, A View From the Reality-Based Universe"). By the way, these same products also cure cancer, diabetes, hemorrhoids, halitosis and the heartbreak of psoriasis. So you really get quite a bang for your buck.

Returning to a reality-based universe, although we still can't eradicate HIV, we are indeed closing in on a cure from several different paths. The simplest and most direct strategy for eradicating the virus involves administering a treatment to the HIVer that would wake up all the infected cells in the latent HIV reservoir so that they would start producing virus. ART would shut down viral replication, and the cell would eventually die, as it would no longer be dormant (asleep). This proposed scenario was attempted most notably with interleukin-2 and with valproic acid.

We've identified two main problems with this approach. First, the treatment "alarm clocks" designed to wake up the sleeping virus in CD4 cells would need to activate every single infected dormant CD4 cell in the entire body. If you missed any and then stopped ART, HIV could come roaring back once again. Second, the treatments tried so far act exclusively on the resting CD4 cell population. Unfortunately we are now realizing that these dormant long-lived cells are not the only reservoir for latent HIV.

A growing number of experts believe that a "functional cure," whereby HIV is disabled and/or the immune system is strengthened sufficiently to hold off disease progression when ART is discontinued, is an achievable goal in the very foreseeable future. This ART-free remission ("functional cure") may be a more realistic goal than the complete eradication of HIV. One mechanism for strengthening the immune system is therapeutic vaccination. Such a vaccine would not eradicate HIV, but might stimulate immune defenses to be more effective against HIV. This type of therapy would have the potential to transform HIVers into "long-term nonprogressors." There are a number of promising therapeutic vaccine candidates, but vaccine research is both time and labor intensive, and this experimental approach probably won't be ready for prime time any time soon.

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There are other very novel strategies also being cautiously evaluated. One research company has developed a technology, which is now in very early clinical trials, that to some extent mimics what happened in the now famous "Berlin Patient". This strategy utilizes zinc fingers, which are in essence tiny molecular scissors that are designed to snip the CCR5 gene (not the receptor itself, but the gene that codes for the receptor) off the DNA within CD4 cells that have been removed from the HIVer's body and expanded (artificially multiplied). These genetically altered CD4 cells, which are now resistant to CCR5 HIV viruses, are then infused back into the patient. Whether the manipulated cells will survive and function normally is not yet known.

Just prior to the International AIDS Conference in Vienna in July 2010, the International AIDS Society (IAS) held a workshop titled "Towards a Cure: HIV Reservoirs and Strategies to Control Them." During the workshop information was presented about drugs called HDAC inhibitors, which have been shown to activate latent HIV in the test tube. Representatives from Merck discussed a trial of an HDAC inhibitor and another drug called a protein kinase C activator in monkeys. The approach was successful in decreasing viral load, but did not prevent viral rebound when ART was interrupted.

HIV expert Brigitte Autran presented the design of two promising clinical trials (Eramune 01 and 02) that will evaluate the effect of adding certain immune-based therapies to ongoing ART. Eramune 01 involves intensifying ART and stimulating the immune system with interleukin-7 (IL-7), a bioactive agent that may be able to deplete latent HIV from memory CD4 T-cells. Eramune 02 will test a therapeutic vaccine plus intensified ART. The goal is to strengthen the immune response to specifically recognize and destroy HIV-infected cells. Details of both clinical trials are available in the clinical trials database section at www.clinicaltrials.gov.

Other indications that the search for a cure has been elevated to a top-of-the-agenda item include:

The National Institutes of Health has announced an eight-million-dollar grant program called the "Martin Delaney Collaboratory: Toward an HIV Cure." This program offers grants to research institutions that partner with industry to solve the key problems standing in the way of a cure for HIV.

The non-profit organization amfAR has instituted a targeted program also supporting collaborative cure-related research called the amfAR Research Consortium for HIV Eradication (ARCHE).

TAG (Treatment Action Group) is planning a workshop with amfAR focusing on clinical and regulatory issues related to HIV-cure strategies and clinical trials in an effort to accelerate and streamline the cure-research effort.

There is no doubt that in the search for a cure we often take two steps forward and then one step back. However, we are now certain that we are stepping on the correct path and the pace of our steps is dramatically quickening. The take-home message: A CURE IS NOT ONLY POSSIBLE; IT'S FINALLY IN SIGHT AND HOPEFULLY SOON WITHIN REACH!

Want to get in touch with Dr. Bob? You can reach him through his "Ask the Experts" forum, by sending a message to the Robert James Frascino AIDS Foundation, or by leaving a comment for him below. (If it's a private message, or if it includes personal info such as your e-mail address or phone number, we won't post the comment, but we will send it along to him.)

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